In an effort to remove residual palladium from a drug
candidate
prepared by palladium-catalyzed indolization, many
treatments
were examined. The most effective treatment was to
precipitate
palladium from solution using
2,4,6-trimercapto-s-triazine
(TMT), which reduced palladium levels from 600−650 ppm
to
20−60 ppm in an isolated indole intermediate.
Subsequent
crystallizations routinely afforded active pharmaceutical
ingredient with <1 ppm of palladium. TMT treatment
should
prove useful to reduce the concentration of residual
palladium
in other reactions.
5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride (1) facilitates
5-HT neurotransmission and was an antidepressant drug candidate.
The
development of a safe, rugged process for the large-scale,
chromatography-free preparation of this compound is described. The main areas of optimization included a
Fischer
indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to
prepare the drug substance.
The final step of the semisynthetic route to paclitaxel involves cleavage of the triethylsilyl (TES) protecting group from the C-7 hydroxyl group. Paclitaxel is an extremely complex molecule, and standard deprotection conditions led to formation of several impurities. Trifluoroacetic acid in aqueous acetic acid was found to be very effective in the cleavage of the TES group without compromising the quality of the product.
A safe, rugged process for the manufacture of a Monopril
intermediate using a trimethylsilyl-mediated Arbuzov
reaction
was developed. The problems encountered and overcome
in
iterations from pilot plant to manufacturing are described.
The
final process gives high-quality product (99.9% purity) in
82%
yield. One key was developing an addition sequence to
allow
for the safe control of the reaction exotherm, complicated
by
the reflux temperature which decreased with conversion of
reagents. Quantitative assessment of the reaction boiling
point
and exotherm led to the selection of the best addition and
heating protocol. The output quality was assured by
development of a thermally controlled process that crystallized
the
product without passing through an intermediate oil
dispersion.
Alternative conditions for safe control of the exotherm
are
suggested. Routine safety testing is demonstrated to be
critical
for rapid development of a safe, optimized process.
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